Osteoporosis- related fractures result from a combination of de creased BMD and a deterioration in bone microarchitecture.
A BMD T score of – 2.5 or less indicating osteoporosis is present in about 50% of patients presenting with wrist, spine, or hip fracture. A BMD below average for age can be considered a consequence of inadequate accumulation of bone in young adult life (low peak bone mass) or of excessive rates of bone loss. The microarchitectural changes occur in parallel with the bone loss but will be considered separately.
Determinants of Peak Bone Mass
The increase in bone mass that occurs during childhood and puberty results from a combination of growth of bone at the endplates (endochondral bone formation) and of change in bone shape (modelling). The rapid increase in bone mass at puberty is associated with an increase in sex hormone levels and the closure of the growth plates. Within 3 years of menarche, there is little further increase in bone mass. The small increase in BMD over the next 5– 15 years is referred to as ‘consolidation’. The resulting peak bone mass is achieved by age 20– 30 years old.
Genetic factors are the main determinants of peak bone mass. This has been shown by studies made on twins or on mother– daughter pairs. Hereditability appears to account for about 50– 85% of the variance in bone mass, depending on the skeletal site. Variants in the genes encoding factors known to regulate bone mass (such as oestrogen receptor- α (ERα), vitamin D receptor, transforming growth factor- β (TGFβ), low- density lipoprotein receptor- related protein 5 (LRP5) and LRP6 (both involved in WNT signalling) and bone matrix components (e.g. collagen type I α1) were found to be associated with bone mass and fracture risk, but these variants could be used to explain only very little of the interindividual variation. The non- genetic factors include low calcium intake during childhood, low body weight at maturity and at 1 year of life, sedentary lifestyle, and delayed puberty. Each of these results in decreased bone mass.
Bone Loss
Mechanisms of Bone Loss
Bone loss occurs in the postmenopausal woman as a result of an increase in the rate of bone remodelling and an imbalance between the activity of osteoclasts and osteoblasts. Bone remodelling occurs at discrete sites within the skeleton and proceeds in an orderly fashion with bone resorption always being followed by bone formation, a phenomenon referred to as ‘coupling’. In cortical and cancellous bone, the sequence of bone remodelling is similar. The quiescent bone surface is converted to activity (origination) and the osteoclasts resorb bone (progression) forming a cutting cone (cortical bone) or a trench (cancellous bone). The osteoblasts synthesize bone matrix which subsequently mineralizes. The sequence takes up to 8 months. If the processes of bone resorption and bone formation are not matched then there is ‘remodelling imbalance’. In postmenopausal women, this imbalance is magnified by the increase in the rate of initiation of new bone remodelling cycles (activation frequency).
Remodelling imbalance results in irreversible bone loss. There are two other causes of irreversible bone loss, referred to as ‘remodelling errors’. First is excavation of overlarge haversian spaces in cortical bone. Radial infilling is regulated by signals from the outer most osteocytes and is generally no more than 90 µm. Hence, large external diameters, which may simply occur randomly, lead to large central haversian canals, which then accumulate with age, leading to increased cortical porosity. In a similar way, osteoclast penetration of trabecular plates, or severing of trabecular beams, removes the scaffolding needed for osteoblastic replacement of resorbed bone. In both ways random remodelling errors tend to reduce both cancellous and cortical bone density and structural integrity.
Causes of Bone Loss
Oestrogen Deficiency
Bone loss in the postmenopausal woman occurs in two phases. There is a phase of rapid bone loss that lasts for 5 years (about 3% per year in the spine). Subsequently, there is lower bone loss that is more generalized (about 0.5% per year at many sites). This slower phase of bone loss affects men, starting at about age 55 years. The rapid phase of bone loss in women is caused by oestrogen deficiency. The circulating level of oestradiol decreases by 90% at the time of the menopause. This bone loss can be prevented by the ad ministration of oestrogen and progestins to the postmenopausal woman. It has been estimated that this rapid phase of bone loss contributes 50% to the spinal bone loss across life in women. The main effect of oestrogen deficiency is on bone, where it increases activation frequency, and may contribute to the remodelling imbalance. Oestrogen deficiency may increase bone resorption by stimulating the synthesis of RANKL by osteoblasts (or their precursors). RANKL binds to its receptor RANK on the osteoclast and promotes differentiation to osteoclasts, increases osteoclast activity, and inhibits osteoclast apoptosis. Oestrogen deficiency also increases the apoptosis of osteoblasts and osteocytes.
Oestrogen deficiency may be a determinant of bone loss in men. Decreased BMD has been reported in men with an inactivating mutation of the genes for the oestrogen receptor or for aromatase (the enzyme that converts androgens to oestrogens). In older men, oestrogen levels correlate more closely with BMD than testosterone levels. In men with osteoporosis, oestradiol (but not testosterone) levels have been reported to be decreased.
Ageing
The slow phase of bone loss is attributed to age- related factors such as an increase in parathyroid hormone (PTH) levels (Figure 1) and to osteoblast senescence. An increase in PTH levels (and action) occurs in both men and women with ageing. PTH levels correlate with those of biochemical markers of bone turnover and both may be returned to those found in young adults by the intravenous infusion of calcium. The increase in PTH results from decreased renal calcium reabsorption and decreased intestinal calcium ab sorption. The latter may result from vitamin D deficiency (e.g. in the housebound elderly), decreased 1α- hydroxylase activity in the kidney resulting in decreased synthesis of 1,25- dihydroxyvitamin D, or resistance to vitamin D. Whatever the cause, a diet high in calcium returns both PTH and bone turnover markers to levels found in healthy young adults. It has been proposed that the age- related increase in PTH could result from indirect effects of oestrogen deficiency. This proposal is based on the following evidence. In older women treated with oestrogen, there is a decrease in bone turnover markers and PTH levels; there is an increase in calcium absorption, possibly mediated by an increase in 1,25- dihydroxyvitamin D; there is an increase in the PTH- independent calcium reabsorption in the kidney; and there is a decrease in the parathyroid secretory reserve.
Fig1. The causes of bone loss with ageing.
Accelerating Factors
A number of diseases and drugs are clearly related to accelerated bone loss (Box 1). Their effects are superimposed on those described just now. Thus, a patient starting on corticosteroid therapy is more likely to have an osteoporosis- related fracture if she has low BMD resulting from low peak bone mass and the accelerated bone loss of the menopause.
Box1. Risk factors for osteoporosis in postmenopausal women
identification of Mechanism of Bone Loss in an individual
In a woman presenting with osteoporosis at age 70 years it is often possible to identify several reasons for the low BMD (Figure 2). Some of these may be identified from history taking (early menopause, drugs that accelerate bone loss), but some cannot be identified in retrospect (low peak bone mass and rapid losers).
Fig2. The possible causes of low bone mass in a 70- year- old woman. Note how peak bone mass is attained about the age of 30 years and the phase of accelerated bone loss begins at the menopause. The lower the bone density falls, the greater the risk of fracture.
other Determinants of Bone Strength
Bone Geometry Bone geometry has a major effect on fracture risk. One example is hip axis length, the distance from the lateral surface of the trochanter to the inner surface of the acetabulum, along the axis of the femoral neck. Short hip axis length results in an architecturally stronger structure for any given bone density. This is probably the reason why Japanese and other Orientals have about half the hip fracture rate of Caucasians, despite similar bone density values.
Fatigue Damage
Fatigue damage consists of ultramicroscopic rents in the basic bony material, resulting from the inevitable bending that occurs when a structural member is loaded. Fatigue damage is the principal cause of failure in mechanical engineering structures; its prevention is the responsibility of the remodelling apparatus which detects and re moves fatigue- damaged bone. Fractures related to fatigue damage occur whenever the damage occurs faster than remodelling can re pair it or whenever the remodelling apparatus is defective. March fractures and the fractures of radiation necrosis are well- recognized examples of fractures due to these two mechanisms.
Loss of Trabecular Connectivity
Bone structures loaded vertically, such as the vertebral bodies and femoral and tibial metaphyses, derive a substantial portion of their structural strength from a system of horizontal, cross- bracing trabeculae which support the vertical elements and limit lateral bowing and consequent snapping under vertical loading. Severance of such trabecular connections is known to occur preferentially in postmenopausal women and is considered to be an important reason for the large female/ male preponderance of low- trauma vertebral fractures.
